Despite the availability of drugs that can cure tuberculosis, 1.4 million people died of tuberculosis in 2011. Although tuberculosis incidence has declined in most developed areas of the world, South Africa and other regions have been unable to achieve tuberculosis control. The development and transmission of drug-resistant Mycobacterium tuberculosis strains, continued spread of human immunodeficiency virus (HIV) infection, and significant resource limitations are a few of the complexities that have converged in South Africa. The development of drug-resistance in M. tuberculosis occurs due to spontaneous mutations in the bacterial genome. Mutant strains are selected when single drugs are used for treatment, when insufficient multidrug treatment regimens are administered or supplied, or when patients do not adhere to their treatment. These drug-resistant strains can then be transmitted to other people. Resistance to the two most important first-line drugs, isoniazid and rifampin (defined as multidrug-resistant [MDR] tuberculosis), followed by additional resistance to critical second-line drugs (fluoroquinolones and injectable agents; defined as extensively drug-resistant [XDR] tuberculosis), results in progressively worse treatment outcomes. Fluoroquinolones are critical for the successful treatment of MDR-TB; development of fluoroquinolone resistance is associated with poor outcomes. The current proposal seeks to characterize the incidence and outcomes of fluoroquinolone resistance in patients who have MDR tuberculosis, with particular attention to patients who have fluoroquinolone-susceptible isolates at the time of MDR tuberculosis diagnosis, but who develop fluoroquinolone resistance despite adherence to treatment. The extent of this problem in South Africa, and its effect on clinical outcomes, are unknown. We will first describe the frequency with which fluoroquinolone resistance emerges among patients being treated for MDR tuberculosis. We will then determine risk factors for the development of fluoroquinolone resistance, followed by the effect of fluoroquinolone resistance on clinical outcomes. The study population will be drawn from the South African National Health Laboratory Service database in the Western Cape Province from 2007 to 2011. Molecular epidemiologic techniques will be employed to characterize mutations associated with fluoroquinolone resistance and distinguish between emergence of resistance in the same strain and exogenous reinfection with a fluoroquinolone-resistant strain. The proposed studies will provide new insight into the scope and risk factors fo fluoroquinolone-resistant tuberculosis in a population with a high burden of HIV as well as MDR and XDR tuberculosis. The results will allow for implementation of strategies to prevent the development of fluoroquinolone resistance and protect this class of drugs for effective anti-tuberculosis therapy.